Project Abstract Major depression is a mental disorder reported to affect approximately 16.2 million adults aged 18 years or older in the United States in 2016. Heritability estimates of 31-42% and 48% for depression and loneliness, respectively, indicate a substantial role for genetic and environmental factors in their etiology. Untargeted metabolomics is an emerging approach to quantify large numbers of low molecular weight compounds in a biological sample. Multiple pathways and functional classes are represented, providing a source of biomarkers that can reveal physiologic and cellular processes implicated in the coordinated response to DNA sequence variation and environmental influences occurring over the lifespan. It has previously been demonstrated that this technology can be used to reveal changes in metabolite levels in individuals with common diseases and conditions including cardiovascular disease, type 2 diabetes, chronic kidney disease, cognitive decline, and Alzheimer?s disease and dementia. In this study, we propose to analyze the association of serum metabolites and depression, social isolation, and perceived social support in midlife. This will be accomplished in the setting of the Atherosclerosis Risk in Communities (ARIC) Study, a prospective biracial cohort study of atherosclerosis that enrolled 15,792 European American and African American men and women 45 to 64 years at baseline in 1987-1989. ARIC investigators and others have previously shown that these psychosocial factors were associated with increased susceptibility to chronic diseases of late adulthood including cardiovascular disease, and Alzheimer?s disease and dementia. In order to determine whether interindividual variation in metabolite levels is a biological determinant of depression and social isolation the following specific aims will be pursued: identify serum metabolites that are associated with depression, social isolation, and social support (Aim 1); evaluate the relationship of common and rare DNA sequence variation with the metabolomic signatures associated with depression, social isolation, and social support in Aim 1 by analyzing whole exome sequencing data already available in the ARIC study (Aim 2a), and establish whether the metabolomic signatures identified in Aim 1 are causally related by examining the association between the genetic variants identified in Aim 2a and the corresponding psychosocial factor using a Mendelian randomization approach (Aim 2b); examine the association between the genetic variants found to be related to depression, social isolation, and social support in Aim 2b and incident cardiovascular disease, incident hospitalized dementia, and prevalent Alzheimer?s disease classified based on a comprehensive neurocognitive assessment in all ARIC participants with exome sequencing (Aim 3). The long-term goals of this research are to further understand the underlying biological mechanisms, and to discover biomarkers to identify high-risk individuals who would benefit from interventions to prevent the spectrum of adverse health consequences that become clinically apparent at older ages.